Shared and divergent features of the immune response to acute and chronic Trypanosoma cruzi infection in mice revealed by cardiac transcriptomics

Abstract

Chagas disease is caused by infection with Trypanosoma cruzi and can result in chronic cardiomyopathy. However, the molecular programmes that define infected cardiac tissue, and how they change as the host-parasite relationship moves from acute pathogenic infection to long-term persistence, remain incompletely understood. Here, we used RNA sequencing to characterise host transcriptional responses in cardiac tissue during both acute and chronic infection in a mouse model. Cardiac parasite distribution was defined using bioluminescence imaging and histology, and RNA sequencing was performed on anatomically standardised cardiac tissue samples collected at both stages. Acute infection was associated with a broad interferon-driven immune activation, whereas during chronic infection this network contracted, with preservation of a tightly connected antigen presentation core centred on major histocompatibility complex genes and immunoproteasome components. Genes associated with extracellular matrix remodelling and fibrosis were not broadly activated. These findings indicate that reduced, but sustained immune activation, rather than widespread fibrotic transcriptional remodelling, represents a prominent feature of cardiac tissue in chronically infected mice. They identify a transition from an overtly inflammatory, pathogen-driven acute response to a more restricted chronic host-parasite equilibrium in which immune surveillance remains transcriptionally active despite very low and spatially intermittent cardiac infection. We identified a conserved 20-gene signature shared between acute and chronic stages. This overlap is consistent with continued or episodic parasite-derived stimulation and/or intrinsic host mechanisms that maintain cardiac immune surveillance. Thus, chronic T. cruzi infection can be viewed as a persistent host-parasite association in which biological coexistence does not imply benignity: immune containment and parasite persistence can occur alongside cumulative cardiac injury.